Neural tube defects (NTDs) are one of the most common crippling birth defects with an overall incidence in the United States of 1-2 per 1,000 births. NTDs include all congenital anomalies that involve lack of closure of the developing neural tube during embryogenesis. Roughly half of NTDs result in meningomyelocele (an exposed area of the spinal cord) which is compatible with life but usually (99% of the time) results in handicap. The other half of the time, NTDs result in anencephaly (exposed or absent brain) which is lethal. NTDs are known to occur secondary to a combination of genetic and environmental factors. Our study will identify genes that contribute to the occurrence of meningomyelocele [also termed spina bifida (SB)]. The search for SB-causing genes is complicated by: the lack of clear-cut inheritance in SB, the paucity of multigenerational SB families, and the unknown contribution to the phenotype from environmental factors. For these reasons, our main subject population is a large number (500) of simplex SB families (families with a single affected individual) who will be tested for genetic associations. A nonparametric linkage technique, the transmission disequilibrium test (TDT) will be our method of analysis. We propose a two-pronged attack: we will test approximately 100 candidate genes and we will institute a genome-wide search at 10 cM distances. The five categories of candidate genes include: genes involved in folate metabolism, genes implicated from animal models, HOX and PAX genes, growth factor and growth factor receptor genes and proto-oncogenes. The data will be analyzed in multiple ways including by ethnicity and level of defect. Correlations will also be made between genotype and findings from the other Projects. Follow-up of positive associations will be verified in several ways: additional markers will tested in the candidate gene or region, markers will be tested in those multigenerational families identified, and markers will be tested in an independent sample set (200 families) that will be gradually collected and stored until needed.